N- and S-donor leaving groups in triazole-based ruthena(ii)cycles: potent anticancer activity, selective activation, and mode of action studies

Abstract

A series of 11 novel ruthenium(ii) arene complexes [Ru(p-cym)(trzC^N)L]NO3 based on the cycloruthenated 1,2,3-triazole scaffold (trzC^N) bearing different N- or S-donor leaving groups (L) were prepared. These complexes exhibited strongly diverging pH-dependent stability profiles, but consistently exerted antiproliferative effects in the low micromolar range in three cancer cell lines (A549, SW480, CH1/PA-1). The interaction with biomolecules was correlated to dissociation of the monodentate leaving group. Under oxidative conditions, the stably bound dimethylsulfide ligand (3a) undergoes oxidation, while metal coordination is maintained, affording the labile DMSO complex (3b). Rationalization of the homogenous antiproliferative activities was attempted by determination of the cellular accumulation and lipophilicity indices (φ0). Investigations on their mechanism of action revealed that these metalacycles are inducers of apoptosis, exert a slight antioxidative effect in cell culture studies, but have no DNA intercalatory activity.

Investigations on the Anticancer Potential of Benzothiazole-Based Metallacycles

“…The antiproliferative potency of the investigated compounds, hence, seems to depend on the metal center and increases in the following order: ligands << ruthenium(II) compounds < osmium(II) compounds; with differences in cytotoxicity of the complexes being far less pronounced. The obtained trends are in good agreement with recently reported triazole-based metallacycles, where also a pronounced increase of cytotoxicity upon C,N-coordination to organoruthenium and -osmium moieties was observed (Riedl et al, 2018). With regard to variation of the substituent on the phenylbenzothiazole ligand, consistent structure-activity relationships are difficult to derive, as their impact on cytotoxic potency is rather small.…”

Synthesis, Modification, and Biological Evaluation of a Library of Novel Water‐Soluble Thiopyridone‐Based Organometallic Complexes and Their Unexpected (Biological) Behavior

“…Additional experiments to determine the chromatographic lipophilicity indices ϕ 0 were carried out in order to further support these results. Therefore, a well‐established literature‐known procedure was applied, where the retention times of all complexes was compared to a dead time marker in isocratic RP‐UHPLC runs with different mobile phase compositions . In accordance with the commonly employed log P value, a higher ϕ 0 value correlates to a higher lipophilicity of the respective compound .…”

“…Stock solutions containing the desired complex in DMSO (5 m m ) were diluted with phosphate buffer (pH 7.2) to a final concentration of 500 μ m compound in 1 % DMSO/20 m m buffer and directly analyzed by four different isocratic UHPLC runs (Δ=5 %). The lipophilicity parameters log k w and lipophilicity indices φ 0 were calculated according to literature …”

“…This compound showed preclinical activity against autochthonous colon cancer in a rat model with an efficacy of up to 95 % reduction of tumor volume at a well tolerable dose causing no more than 6 % weight loss . In later studies this lead compound was replaced by its sodium analogue BOLD‐100 (formerly IT‐139 and NKP‐1339; Figure ) due to superior solubility of the latter, which then showed activity in patients with advanced solid tumors, such as non‐small‐cell lung cancer, colorectal carcinoma and gastrointestinal neuroendocrine tumors, in a clinical phase I/II study . Reversible adduct formation with blood proteins is thought to foster accumulation in tumor tissue.…”

“…The development of organometallic complexes brought to light another class of ruthenium compounds, which contain the metal in its +II oxidation state, stabilized via the introduction of a facially coordinated arene ligand . These so‐called “piano‐stool” complexes feature an arene ligand, resembling the stool's seat, and three coordination sites available for mono‐, bi‐ or tridentate ligands, mimicking the legs .…”